Mosquito-borne members of the family Bunyaviridae are recognized as a major cause of pediatric encephalitis in North America with 70-130 symptomatic cases each year. Viruses of clinical importance from the California encephalitis virus group include La Crosse virus (LACV) and Jamestown Canyon (JCV) in the US, and Tahyna virus (TAHV) in Europe. The majority of LACV infections are mild and never reported, however, serologic studies estimate infection rates of 10-30/100,000 in endemic areas. LACV encephalitis has become the most commonly reported pediatric arboviral encephalitis in the US with 70-130 symptomatic cases a year with severe sequelae. Vaccine development: Previously in our laboratory, the full genome sequence of five known human isolates of LACV and of 13 mosquito isolates were analyzed, as well as three isolates of Jamestown Canyon virus. Given our experience with antigenic chimeric viruses of the various flaviviruses, we sought to explore the possibility that we could use an attenuated LACV as a backbone to create antigenic chimeric viruses in which the coding region of the M segment of LACV is replaced with that of a second bunyavirus. In our efforts to create live-attenuated viral vaccine candidates for this virus group, we previously generated a recombinant La Crosse virus expressing the attachment glycoproteins of Jamestown Canyon virus. The JCV/LACV chimeric virus contains full-length S and L segments derived from LACV. In the M segment, the ORF of LACV is replaced with that derived from JCV and is flanked by the non-coding regions of LACV. We demonstrated that chimerization did not affect the growth of the chimeric virus in tissue culture, and the virus remains highly infectious and immunogenic in Swiss Webster mice. Although both LACV and JCV parental viruses are highly neurovirulent in 21 day-old mice, with LD50 values of 1 and 3 PFU, respectively, chimeric JCV/LACV is highly attenuated and does not cause disease even after intracerebral inoculation of 1000 PFU. Parenteral vaccination of mice with 1000 PFU of JCV/LACV protected against lethal challenge with LACV, JCV, and Tahyna virus (TAHV). The chimeric virus was infectious and immunogenic in rhesus monkeys and protected against the development of viremia after JCV challenge. The results of this research were published in 2012. Although we do not currently have plans to further evaluate vaccine candidates for the California encephalitis viruses, the use of the LACV genetic background to deliver M segment protective antigens from pathogenic Bunyaviruses other than JCV could be an efficient method for rapid development of vaccines effective against other pathogenic bunyaviruses, including Rift Valley fever virus and Hantavirus.